Peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory diseases

Abstract

The present invention provides novel peptide inhibitors of the interleukin-23 receptor, and related compositions and methods of using these peptide inhibitors to treat or prevent a variety of diseases and disorders, including inflammatory bowel diseases.

What is claimed is: 
     
         1 . A peptide inhibitor or pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor comprises the amino acid sequence of Formula (II):
   X4-X5-X6-X7-X8-X9-X10-X11  (II)
   wherein   X4 is Pen;   X5 is Asn, or Gln;   X6 is Thr;   X7 is Trp substituted with alkyl;   X8 is Gln, alpha-Me-Lys, alpha-MeLys(Ac), or Lys(Ac);   X9 is Pen;   X10 is Phe substituted with 2-aminoethoxy, or 2-acetylaminoethoxy; and   X11 is 2-Nal, or 1-Nal;   wherein the peptide inhibitor is cyclized via a bond between X4 and X9, and   wherein the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor.   
     
     
         2 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein X5 is Asn. 
     
     
         3 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein X8 is Gln or Lys(Ac). 
     
     
         4 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein X8 is alpha-Me-Lys, or alpha-MeLys(Ac). 
     
     
         5 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein X10 is Phe[4-(2-aminoethoxy)]. 
     
     
         6 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein X7 is Trp substituted with methyl, ethyl, n-propyl, or isopropyl. 
     
     
         7 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein X11 is 2-Nal. 
     
     
         8 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the peptide inhibitor comprises the structure of Formula (Z):
   R 1 —X—R 2   (Z)
   or a pharmaceutically acceptable salt or solvate thereof, wherein   R 1  is a bond, hydrogen, Ac, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12aryl-C1-6alkyl, a C1-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing;   X is the amino acid sequence of Formula (II) and R 2  is OH or NH 2 .   
     
     
         9 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , further comprising a conjugated chemical substituent selected from a lipophilic substituent or a polymeric moiety. 
     
     
         10 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 9 , wherein the conjugated chemical substituent is Ac, Palm, gamaGlu-Palm, isoGlu-Palm, PEG with a molecular weight of 400 Da to 40,000 Da, PEG2-Ac, PEG4-isoGlu-Palm, (PEG) 5 -Palm, succinic acid, glutaric acid, pyroglutaric acid, benzoic acid, IVA, octanoic acid, 1,4 diaminobutane, isobutyl, or biotin. 
     
     
         11 . The peptide inhibitor of  claim 1 , wherein the peptide inhibitor is selected from the group consisting of: 
       
         
           
                 
               
                   (SEQ ID NO: 242) 
                 
                   Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- 
                 
                     
                 
                   aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N- 
                 
                     
                 
                   [BA]-NH 2 ; 
                 
                     
                 
                   (SEQ ID NO: 245) 
                 
                   Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- 
                 
                     
                 
                   aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N- 
                 
                     
                 
                   [(D)Leu]-NH 2 ; 
                 
                     
                 
                   (SEQ ID NO: 248) 
                 
                   Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- 
                 
                     
                 
                   aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N-H- 
                 
                     
                 
                   NH 2 ; 
                 
                     
                 
                   (SEQ ID NO: 249) 
                 
                   Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- 
                 
                     
                 
                   aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N- 
                 
                     
                 
                   [Cit]-NH 2 ; 
                 
                     
                 
                   (SEQ ID NO: 251) 
                 
                   Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- 
                 
                     
                 
                   aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N- 
                 
                     
                 
                   [(D)Val]-NH 2 ; 
                 
                     
                 
                   (SEQ ID NO: 252) 
                 
                   Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- 
                 
                     
                 
                   aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N- 
                 
                     
                 
                   [(D)Lys]-NH 2 ; 
                 
                     
                 
                   (SEQ ID NO: 258) 
                 
                   Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- 
                 
                     
                 
                   aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N- 
                 
                     
                 
                   [(D)Phe]-NH 2 ; 
                 
                     
                 
                   (SEQ ID NO: 284) 
                 
                   Ac-[Pen]-N-T-[W(7-Et)]-[Lys(Ac)]-[Pen]-Phe[4-(2- 
                 
                     
                 
                   aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-N- 
                 
                     
                 
                   [(D)Leu]-NH 2 ; and 
                 
                     
                 
                   (SEQ ID NO: 285) 
                 
                   Ac-[Pen]-N-T-[W(7-n-Pr)]-[Lys(Ac)]-[Pen]-Phe[4- 
                 
                     
                 
                   (2-aminoethoxy)]-[2-Nal]-[[α-MeLys]-[Lys(Ac)]-N- 
                 
                     
                 
                   [(D)Leu]-NH 2 ; 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         or a pharmaceutically acceptable salt or solvate thereof; 
         wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond. 
       
     
     
         12 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the bond between X4 and X9 is a disulfide bond. 
     
     
         13 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein X7 is Trp substituted with alkyl at 4-, 6-, or 7-position. 
     
     
         14 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein X7 is W(1-Me), W(4-Me), W(6-Me), W(6-Et), W(7-Me), W(7-Et), W(7-n-Pr), or W(7-i-Pr). 
     
     
         15 . The peptide inhibitor of  claim 1 , or pharmaceutically acceptable salt or solvate thereof, wherein:
 X4 is Pen;   X5 is Asn;   X6 is Thr;   X7 is Trp substituted with alkyl;   X8 is Gln, or Lys(Ac);   X9 is Pen;   X10 is Phe[4-(2-aminoethoxy)]; and   X11 is 2-Nal;   wherein the peptide inhibitor is cyclized via a bond between X4 and X9, and   wherein the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor.   
     
     
         16 . The peptide inhibitor of  claim 15 , or pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor is:
 Ac-[Pen]-NT-[W(7-Me)]-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]—NN—NH 2  (SEQ ID NO: 6);   Ac-[Pen]-N-T-[W(7-Et)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]—N—[(D)Leu]-NH 2  (SEQ ID NO: 284); or   Ac-[Pen]-N-T-[W(7-n-Pr)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]—N—[(D)Leu]-NH 2  (SEQ ID NO: 285);   wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond.   
     
     
         17 . The peptide inhibitor of  claim 1 , or pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor is:
 Ac-[Pen]-NT-[W(7-Me)]-Gln-[Pen]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys(Ac)]—NN—NH 2  (SEQ ID NO: 6),   wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond.   
     
     
         18 . The peptide inhibitor of  claim 1 , or pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor is:
 Ac-[Pen]-N-T-[W(7-Et)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]—N—[(D)Leu]-NH 2  (SEQ ID NO: 284),   wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond.   
     
     
         19 . The peptide inhibitor of  claim 1 , or pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor is:
 Ac-[Pen]-N-T-[W(7-n-Pr)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]—N—[(D)Leu]-NH 2  (SEQ ID NO: 285),   wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond.   
     
     
         20 . A pharmaceutical composition comprising the peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , and a pharmaceutically acceptble carrier, excipient, or diluent. 
     
     
         21 . The pharmaceutical composition of  claim 20 , further comprising an enteric coating.